Each year over 30 million Americans present to trauma centers, emergency departments, and other acute care medical settings (i.e., trauma care systems) for the treatment of physical injuries. Multiple chronic conditions including Posttraumatic Stress Disorder (PTSD), alcohol and drug use problems, depression and associated suicidal ideation, pain and somatic symptoms, and pre-existing chronic medical conditions are endemic among physical trauma survivors with and without traumatic brain injuries (TBI). Enduring PTSD and comorbidity are associated with marked functional impairments and societal costs. Evidence-based treatments for PTSD and comorbidity exist, but have yet to be broadly implemented throughout trauma care systems. The challenges presented by this constellation of PTSD and comorbid conditions in survivors of TBI and non-TBI related injury, require novel research approaches that cut across the traditional domains of multiple NIH institutes. The overarching goal of this UH2-UH3 proposal is to work synergistically with the NIH HCS Research Collaboratory to efficiently develop and implement an innovative large scale, pragmatic clinical trial that directly informs national trauma care system policy. The study team is proposing a 20 trauma center cluster randomized trial that incorporates Collaboratory-informed state-of-the art assessments and information technology innovations. The intervention aims to prevent the development of chronic PTSD and depressive symptoms, alcohol use problems, and enduring physical disability in survivors of both TBI and non-TBI injuries; the intervention also aims to mitigate the impact of the acute injury event on symptom exacerbations in the large subpopulation of patients who already carry a substantial pre-injury burden of multiple chronic medical conditions. The intervention utilizes a computerized decision support tool to flexibly target 3 chronic conditions and includes care management, medication, and psychotherapy elements. At each of the 20 sites an electronic medical record screen will be used to recruit 40 patients with the chronic disease cluster of PTSD and comorbidity for a total of 800 inpatients to be followed over the course of the 12 months after injury hospitalization. The hypotheses are that intervention group patients will demonstrate significant reductions in the symptoms of PTSD, alcohol use, depression, and improved physical function, and that the intervention will be equally effective among injury survivors with and without TBI and with and without chronic medical conditions. Secondary analyses will evaluate the implementation of the intervention using the RE-AIM model augmented by health economic, organizational behavior, and qualitative research methods. Simultaneously, as the investigation is being conducted, the study team will be actively developing an American College of Surgeons' summit agenda targeting the broader aim of engaging trauma care systems nationwide in the research by using pragmatic trial results to directly impact policy mandates and practice guidelines for real-time, work-flow integrated screening, intervention, and quality documentation procedures for PTSD and related comorbidities.